Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([Cl:4])([Cl:3])=O.[CH2:5]1[C@H:17]2[N:8]([CH2:9][C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:15]=3[CH2:16]2)C(=S)[S:6]1>C1(C)C=CC=CC=1.O1CCCC1>[Cl-:3].[Cl:4][C:1]1[S:6][CH2:5][C@@H:17]2[CH2:16][C:15]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[CH2:9][N+:8]=12
Reactant: S=C1SC[C@@H]2Cc3ccccc3CN12
Reactant: O=C(Cl)Cl
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: ClC1=[N+]2Cc3ccccc3C[C@H]2CS1
Product: [Cl-]
Temperature: 20 °C

Procedure:
A solution (20 cc.) containing 2 mols per liter of phosgene in toluene, is added dropwise, in the absence of moisture, whilst stirring and at a temperature of about 20° C ., to a solution of (S)-1,5,10,10a-tetrahydrothiazolo[3,4-b]isoquinoline-3-thione (2.2 g.) in tetrahydrofuran (25 cc.). The mixture becomes cloudy after 15 minutes; it is stirred for 5 hours and then heated to 50° C. for 1 hour. The solvents are evaporated under reduced pressure (25 mm. Hg ) at 60° C. to give (S)-3-chloro-1,5,10,10a-tetrahydrothiazolo[3,4-b]isoquinolinium chloride (2.6 g.) in the form of a very hygroscopic white crystalline powder.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([NH:21][S:22]([CH3:25])(=[O:24])=[O:23])=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH3:28]I>CN(C)C=O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([N:21]([CH3:28])[S:22]([CH3:25])(=[O:24])=[O:23])=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(Cc2ccc(NS(C)(=O)=O)cc2)CC1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(c1ccc(CC2CCN(C(=O)OC(C)(C)C)CC2)cc1)S(C)(=O)=O
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 82.3 %

Procedure:
1-tert-Butoxycarbonyl-4-[4-(methylsulfonyl)aminobenzyl]piperidine (1.4 g, 3.81 mmol) was dissolved in N,N-dimethylformamide (10 mL). To the solution was added 72% sodium hydride in mineral oil (143 mg, 4.29 mmol) under ice cooling, and the mixture was stirred for 10 minutes. To the mixture was added methyl iodide (0.25 mL, 4 mmol), and the mixture was stirred at room temperature for 1 hour. After cooling, the reaction mixture was poured into ice-water (20 mL) and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated sodium chloride solution, dried over anhydrous magnesium sulfate and concentrated under reduced pressure, and the concentrate was purified by silica gel column chromatography (hexane/ethyl acetate=3/2) to give the titled compound (1.20 g) as colorless powdery crystals.
Reaction SMILES: C([O:4][CH2:5][C:6]1[N:10]([C:11]2[CH:16]=[CH:15][C:14]([C:17]#[N:18])=[C:13]([C:19]([F:22])([F:21])[F:20])[CH:12]=2)[N:9]=[N:8][N:7]=1)(=O)C.[Li+].[OH-]>CCO.O>[OH:4][CH2:5][C:6]1[N:10]([C:11]2[CH:16]=[CH:15][C:14]([C:17]#[N:18])=[C:13]([C:19]([F:22])([F:21])[F:20])[CH:12]=2)[N:9]=[N:8][N:7]=1
Reactant: CC(=O)OCc1nnnn1-c1ccc(C#N)c(C(F)(F)F)c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: N#Cc1ccc(-n2nnnc2CO)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 1-[4-cyano-3-(trifluoromethyl)phenyl]-1H-tetrazol-5-yl}methyl acetate (Intermediate 22, 45 g) in EtOH and water (2:1) was added LiOH (8.21 g, 0.342 mol) at 0° C. The reaction was stirred for 3 hours at room temperature. The solvent was removed under vacuum and the residue diluted with DCM, washed with ice-water, saturated aqueous NaHCO3 and brine. The solution was dried over anhydrous Na2SO4 and the solvent removed under vacuum. The crude product was purified by triturating with ether (500 mL) to yield 4-[5-(hydroxymethyl)-1H-tetrazol-1-yl]-2-(trifluoromethyl)benzonitrile as a viscous oil (30 g).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8]2[N:17]=[C:16]([NH:18][C:19]3[CH:20]=[C:21]4[C:25](=[CH:26][CH:27]=3)[N:24]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[N:23]=[CH:22]4)[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]=2)[CH:5]=[CH:6][CH:7]=1.Cl[CH2:36][C:37]1[O:38][CH:39]=[CH:40][N:41]=1.C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[O:38]1[CH:39]=[CH:40][N:41]=[C:37]1[CH2:36][O:1][C:2]1[CH:3]=[C:4]([C:8]2[N:17]=[C:16]([NH:18][C:19]3[CH:20]=[C:21]4[C:25](=[CH:26][CH:27]=3)[N:24]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[N:23]=[CH:22]4)[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: ClCc1ncco1
Reactant: CC(C)(C)OC(=O)n1ncc2cc(Nc3nc(-c4cccc(O)c4)nc4ccccc34)ccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)n1ncc2cc(Nc3nc(-c4cccc(OCc5ncco5)c4)nc4ccccc34)ccc21
Temperature: 70 °C
Reaction time: 1 h

Procedure:
A suspension of tert-butyl 5-(2-(3-hydroxyphenyl)quinazolin-4-ylamino)-1H-indazole-1-carboxylate (100 mg, 0.22 mmol), 2-(chloromethyl)oxazole (31 mg, 0.26 mmol), KI (44 mg, 0.27 mmol), and K2CO3 (122 mg, 0.88 mmol) in dry DMF (1.5 mL) was stirred at 70° C. for 1 h. The mixture was poured into water, filtered, dried under high vacuum for several hours to afford tert-butyl 5-(2-(3-(oxazol-2-ylmethoxy)phenyl)-quinazolin-4-ylamino)-1H-indazole-1-carboxylate.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([N:10]2[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][CH2:18][CH2:19][N:20]3[C:29](=[O:30])[CH2:28][C:23]4([CH2:27][CH2:26][CH2:25][CH2:24]4)[CH:22](C(OOCC4C=CC([N+]([O-])=O)=CC=4)=O)[C:21]3=[O:45])[CH2:12][CH2:11]2)=[N:2]1.CO.C1C[O:51]CC1>[Pd]>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([N:10]2[CH2:11][CH2:12][N:13]([CH2:16][CH2:17][CH2:18][CH2:19][N:20]3[C:29](=[O:30])[CH2:28][C:23]4([CH2:27][CH2:26][CH2:25][CH2:24]4)[CH:22]([OH:51])[C:21]3=[O:45])[CH2:14][CH2:15]2)=[N:2]1
Reactant: O=C(OOCc1ccc([N+](=O)[O-])cc1)C1C(=O)N(CCCCN2CCN(c3nsc4ccccc34)CC2)C(=O)CC12CCCC2
Reactant: C1CCOC1
Agent: [Pd]
Solvent: CO
Product: O=C1CC2(CCCC2)C(O)C(=O)N1CCCCN1CCN(c2nsc3ccccc23)CC1
Reaction time: 1.5 h
Yield: 69 %

Procedure:
A mixture of 8-[4-[4-(1,2-benzisothiazol-3-yl)-1piperazinyl]butyl]-6-(4-nitro-benzyloxycarboxy)-8-azaspiro [4.5]decane-7,9-dione (1.98 g, 3.12 mmol) and 10% Pd/C (0.75 g) in MeOH-THF (2:1, 30 mL) was hydrogenated in a Parr shaker at 55 psi for 1.5 h. An additional 1.25 g of 10% Pd/C was added and hydrogenation was continued at 55 psi for 1 h. The resulting mixture was filtered through a pad of Celite and the pad was washed with EtOAc. The filtrate was evaporated to give a gum which was purified by flash chromatography (EtOAc) to give the title compound (0.98 g, 69%) as a solid. An analytical sample was crystallized from EtOAc/hexane to give pale yellow crystals, m.p. 151° C.; IR (neat) 3430, 1728, 1673 cm-1 ; 1H NMR (CDCl3) δ 7.90-7.76 (m, 2H), 7.49-7.29 (m, 2H), 4.18 (s, 1H), 3.82-3.69 (m, 2H), 3.59-3.54 (m, 5H), 2.79, 2.52 (AB q, J=17.4 Hz, 2H), 2.75-2.66 (m, 4H), 2.49-2.44 (m, 2H), 2.11-1.98 (m, 1H), 1.74-1.19 (b m, llH);
Reaction SMILES: Br[Si](C)(C)C.C([O:8][P:9]([CH2:14][O:15][CH2:16][CH2:17][N:18]1[CH:26]=[N:25][C:24]2[C:23](=[O:27])[NH:22][C:21]([NH2:28])=[N:20][C:19]1=2)([O:11]CC)=[O:10])C.O.CC(C)=O>CN(C=O)C>[P:9]([CH2:14][O:15][CH2:16][CH2:17][N:18]1[CH:26]=[N:25][C:24]2[C:23](=[O:27])[NH:22][C:21]([NH2:28])=[N:20][C:19]1=2)([OH:10])([OH:11])=[O:8]
Reactant: CCOP(=O)(COCCn1cnc2c(=O)[nH]c(N)nc21)OCC
Agent: C[Si](C)(C)Br
Solvent: CC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: Nc1nc2c(ncn2CCOCP(=O)(O)O)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 4 h
Yield: 92.8 %

Procedure:
Bromotrimethylsilane (2.77 g, 18.1 mmol) was added dropwise over 2 min to a solution of 9-(2'-(diethylphosphonomethoxy)ethyl)guanine (0.625 g, 1.80 mmol) in 15 mL of dry DMF at rt under argon in a foil-covered flask. The reaction mixture was stirred at rt for 4 h and then volatiles were removed in vacuo to give a viscous yellow oil. The residue was treated with 5 mL of water, giving immediate formation of a white solid. 5 mL more water was added, followed by 10 mL of acetone; the precipitate was collected by filtration. The crude product was purified by recrystallization from water/ethanol to give 0.483 g of 9-(2-(phosphonomethoxy)ethyl)guanine as white crystals, m.p. >260°.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[C:7]([C:15]2[N:19]=[CH:18][N:17](/[CH:20]=[CH:21]\[C:22]([NH:24][NH2:25])=[O:23])[N:16]=2)[CH:8]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:10]=1)(=[O:4])=[O:3].[CH3:26]OC(OC)OC.CS(O)(=O)=O.CO>O.ClCCl>[CH3:1][S:2]([C:5]1[CH:6]=[C:7]([C:15]2[N:19]=[CH:18][N:17](/[CH:20]=[CH:21]\[C:22]3[O:23][CH:26]=[N:25][N:24]=3)[N:16]=2)[CH:8]=[C:9]([C:11]([F:12])([F:14])[F:13])[CH:10]=1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)c1cc(-c2ncn(/C=C\C(=O)NN)n2)cc(C(F)(F)F)c1
Reactant: COC(OC)OC
Agent: CS(=O)(=O)O
Solvent: O
Solvent: CO
Solvent: ClCCl
Product: CS(=O)(=O)c1cc(-c2ncn(/C=C\c3nnco3)n2)cc(C(F)(F)F)c1
Temperature: 80 °C
Yield: 19.5 %

Procedure:
In a 3-neck 25 mL round-bottomed flask, (Z)-3-(3-(3-(methylsulfonyl)-5-(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)acrylohydrazide (0.300 g, 1.0 eq.) under N2 atmosphere was added trimethylorthoformate (0.26 g, 3.0 eq.) and Methane sulphonic acid (0.027 g, 0.1 eq.). Reaction mixture was refluxed at 80° C. for 1 h. The progress of the reaction was followed by TLC analysis on silica gel with 10% methanol: dichloromethane as mobile phase and visualization with UV, SM Rf=0.25 and Product Rf=0.41. The resulting yellow reaction mass was poured in 30 mL water and extracted with 3×20 mL ethylacetate. Organic layer was washed with brine solution followed by drying using anhydrous sodium sulphate. Organic layer was concentrated under reduced pressure to afford 0.250 g of crude compound. The crude reaction mixture was purified by column chromatography using silica 60/120 using methanol: dichloromethane as mobile phase. The column (2×10 cm) was packed in dichloromethane and started eluting in Methanol in gradient manner starting with fraction collection (25-mL fractions) from 1.5% to 2.5% methanol in dichloromethane. Compound started eluting with 1.5% methanol in dichloromethane. Fraction containing such TLC profile was collected together to obtain pure compound (0.060 g), Yield (20%) 1H NMR (400 MHz, CDCl3) δ 9.76 (S, 1H), 7.2-8.6 (m, 7H), 7.39-7.41 (d, J=10.8, 1H), 5.58-5.88 (d, J=11.2 Hz, 1H), 5.39 (S, 2H), 4.70-4.73 (m, 1H), 1.39-1.41 (d, 6H): LCMS for C21H19F3N4O3 [M+1]+ 432.4 found 432.96 at RT 4.217 min.
Reaction SMILES: [C:1]([CH:5]1[N:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:11][CH:10]2[N:6]1[CH2:7][CH2:8][CH2:9]2)([O:3]C)=O.N(C[C@@H]1CCCN1)[C:20]1[CH:25]=CC=C[CH:21]=1.[Cl-].[Mg+2].[Cl-].C([Mg]Br)(C)C>C1COCC1.CCOCC>[C:1]([CH:5]1[N:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:11][CH:10]2[N:6]1[CH2:7][CH2:8][CH2:9]2)(=[O:3])[CH:20]([CH3:25])[CH3:21]
Reactant: COC(=O)C1N(c2ccccc2)CC2CCCN21
Reactant: c1ccc(NC[C@@H]2CCCN2)cc1
Agent: CC(C)[Mg]Br
Agent: [Cl-]
Agent: [Mg+2]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(C)C(=O)C1N(c2ccccc2)CC2CCCN21
Temperature: -70 °C
Yield: 79 %

Procedure:
2-Carbomethoxy-3-phenyl-1,3-diazabicyclo[3,3,0]octane prepared from 637 mg of (S)-2-(anilinomethyl)pyrrolidine was dissolved in 18 ml of THF, then admixed with 378 mg of anhydrous magnesium chloride, and refluxed for 10 minutes by heating. To the mixture cooled to -70° C., was added dropwise an ether solution containing 1.37 equivalents of isopropylmagnesium bromide. The resulting mixture was treated as in Example 12 to obtain 731 mg (79%) of 2-isobutyryl-3-phenyl-1,3-diazabicyclo[3,3,0]octane. NMR peaks: δ(ppm)=0.9 (3H, doublet), 1.1 (3H, doublet), 1.5-2.2 (4H, multiplet), 2.4-3.3 (4H, multiplet), 3.5-3.9 (2H, multiplet), 4.4 (1H, singlet), 6.2-7.1 (5H, multiplet).
Reaction SMILES: [OH:1][C@@H:2]([C@H:4]1[C:36](=[O:37])[N:6]2[C:7]([C:23]([O:25]CC3C=CC([N+]([O-])=O)=CC=3)=[O:24])=[C:8]([C:11]3[S:15][C:14]4=[C:16]([S:19][CH2:20][CH2:21][OH:22])[N:17]=[CH:18][N:13]4[CH:12]=3)[C@H:9]([CH3:10])[C@H:5]12)[CH3:3].P([O-])([O-])([O-])=O.[Na+:43].[Na+].[Na+].[H][H]>C1COCC1.[Pd]>[OH:1][C@@H:2]([C@H:4]1[C:36](=[O:37])[N:6]2[C:7]([C:23]([O-:25])=[O:24])=[C:8]([C:11]3[S:15][C:14]4=[C:16]([S:19][CH2:20][CH2:21][OH:22])[N:17]=[CH:18][N:13]4[CH:12]=3)[C@H:9]([CH3:10])[C@H:5]12)[CH3:3].[Na+:43]
Reactant: [H][H]
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(c3cn4cnc(SCCO)c4s3)[C@H](C)[C@H]12
Agent: [Pd]
Agent: O=P([O-])([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)[O-])=C(c3cn4cnc(SCCO)c4s3)[C@H](C)[C@H]12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
4-Nitrobenzyl (1S,5R,6S)-6-((1R)-1-hydroxyethyl)-2-[7-(2-hydroxyethyl)thioimidazo[5,1-b]thiazol-2-yl]-1-methyl-1-carbapen-2-em-3-carboxylate (48.4 mg) was dissolved in 2.5 ml of THF and 2.5 ml of a 1/15 M sodium phosphate buffer (pH 6.6). 10% Pd-C (50 mg) was added to the solution. The air in the reaction vessel was replaced by hydrogen, and the contents of the reaction vessel were stirred at room temperature for 2 hr. The catalyst was removed by filtration on Celite, and was washed with water. The filtrate was washed with ethyl acetate, and was then concentrated under the reduced pressure to bring the volume of the solution to about 1 ml. The residue was purified by column chromatography on Cosmosil 40C18-PREP (20% aqueous methanol solution) to prepare 15.8 mg of the title compound.
Reaction SMILES: [OH:1][CH:2]1[CH2:5][N:4]([C:6]2[CH:11]=[CH:10][C:9]([N+:12]([O-])=O)=[CH:8][N:7]=2)[CH2:3]1.[H][H]>C(O)C.[Pd]>[NH2:12][C:9]1[CH:8]=[N:7][C:6]([N:4]2[CH2:3][CH:2]([OH:1])[CH2:5]2)=[CH:11][CH:10]=1
Reactant: O=[N+]([O-])c1ccc(N2CC(O)C2)nc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: Nc1ccc(N2CC(O)C2)nc1

Procedure:
A suspension of 0.34 g (1.74 mmol) of 2-(3-hydroxyazetidin-1-yl)-5-nitropyridine, prepared in the preceding stage, and 9 mg of Pd/C at 10% in 10 mL of ethanol is stirred vigorously at 20° C. under 5 atm of hydrogen for 4 hours. After this time, the mixture is filtered on a Celite pad and then concentrated at reduced pressure. The resultant product is purified by chromatography on a silica column, eluting with a mixture of dichloromethane and methanol. We thus obtain 0.1 g of the expected product, which will be used as it is in the rest of the synthesis.
Reaction SMILES: [CH2:1]([N:3]1[C:8]2[N:9]=[C:10]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([N:20]4[CH2:25][CH2:24][N:23]([CH3:26])[CH2:22][CH2:21]4)=[CH:16][CH:15]=3)[N:11]=[CH:12][C:7]=2[CH:6]=[C:5](B(O)O)[C:4]1=[O:30])[CH3:2].Br[C:32]1[S:36][C:35]([C:37]2[S:38][CH:39]=[CH:40][CH:41]=2)=[CH:34][CH:33]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(COC)OC.O>[S:36]1[C:32]([C:5]2[C:4](=[O:30])[N:3]([CH2:1][CH3:2])[C:8]3[N:9]=[C:10]([NH:13][C:14]4[CH:19]=[CH:18][C:17]([N:20]5[CH2:25][CH2:24][N:23]([CH3:26])[CH2:22][CH2:21]5)=[CH:16][CH:15]=4)[N:11]=[CH:12][C:7]=3[CH:6]=2)=[CH:33][CH:34]=[C:35]1[C:37]1[S:38][CH:39]=[CH:40][CH:41]=1
Reactant: Brc1ccc(-c2cccs2)s1
Reactant: CCn1c(=O)c(B(O)O)cc2cnc(Nc3ccc(N4CCN(C)CC4)cc3)nc21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: CCn1c(=O)c(-c2ccc(-c3cccs3)s2)cc2cnc(Nc3ccc(N4CCN(C)CC4)cc3)nc21
Yield: 33.5 %

Procedure:
8-Ethyl-2-[4-(4-methyl-piperazin-1-yl)-phenylamino]-7-oxo-7,8-dihydro-pyrido[2,3-d]pyrimidine-6-boronic acid (21, 71 mg, 0.17 mmol), 5-bromo-2,2′-bithiophene (47 mg, 0.19 mmol), sodium carbonate (55 mg, 0.52 mmol) and Pd(PPh3)4 (20 mg, 0.02 mmol) were mixed under argon in a degassed mixture of dimethoxyethane:water (10:1, 3 mL). The resulting suspension was irradiated for 60 min at 120° C. in a microwave reactor. After completion, the reaction mixture was evaporated and the residue was purified by column chromatography using dichloromethane:methanol (100:5) as eluent. The crude product was triturated with ethyl acetate (10 mL) and collected by filtration. The title compound (30 mg, 0.057 mmol, 33%) was obtained as a yellow solid. ESMS m/z 529 (M+H)+; 1H NMR (400 MHz, DMSO-d6) δ ppm 9.99 (br. s., 1H) 8.81 (s, 1H) 8.45 (s, 1H) 7.72 (d, J=3.8 Hz, 1H) 7.66 (br. s., 2H) 7.51 (dd, J=5.1, 0.9 Hz, 1H) 7.31-7.37 (m, 2H) 7.11 (dd, J=5.0, 3.8 Hz, 1H) 6.95 (d, J=9.0 Hz, 2H) 4.42 (q, J=7.0 Hz, 2H) 3.04-3.17 (m, 4H) 2.42-2.48 (m, 4H) 2.23 (s, 3H) 1.31 (t, J=7.0 Hz, 3H).
Reaction SMILES: Br[C:2]1[C:3]2[C:4]3[CH:17]=[CH:16][S:15][C:5]=3[C:6](=[O:14])[NH:7][C:8]=2[CH:9]=[CH:10][C:11]=1[O:12][CH3:13].CC1(C)C(C)(C)OB([C:26]2[CH:31]=[CH:30][C:29]([C@@H:32]([CH3:42])[CH2:33][NH:34][C:35](=[O:41])[O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[CH:28][CH:27]=2)O1>>[CH3:13][O:12][C:11]1[CH:10]=[CH:9][C:8]2[NH:7][C:6](=[O:14])[C:5]3[S:15][CH:16]=[CH:17][C:4]=3[C:3]=2[C:2]=1[C:26]1[CH:27]=[CH:28][C:29]([C@@H:32]([CH3:42])[CH2:33][NH:34][C:35](=[O:41])[O:36][C:37]([CH3:39])([CH3:38])[CH3:40])=[CH:30][CH:31]=1
Reactant: COc1ccc2[nH]c(=O)c3sccc3c2c1Br
Reactant: C[C@@H](CNC(=O)OC(C)(C)C)c1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Product: COc1ccc2[nH]c(=O)c3sccc3c2c1-c1ccc([C@@H](C)CNC(=O)OC(C)(C)C)cc1
Yield: 48.4 %

Procedure:
Following General Procedure B, 9-bromo-8-methoxy-thieno[2,3-c]quinolin-4(5H)-one (1.2 g, 4.0 mmol) was reacted with (R)-tert-butyl 2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propylcarbamate (2.2 g, 6.1 mmol) to afford the desired product (900 mg, 48%) as a yellow solid: ESI MS m/z 465 [C26H28N2O4S+H]+.
Reaction SMILES: [C:1]([NH:7][C@H:8]([C:13]([OH:15])=[O:14])[CH2:9][C:10]([OH:12])=O)(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].C(O)(=O)C.C(OC(=O)C)(=O)C.CS(O)(=O)=O>C(OCC)(=O)C>[C:1]([NH:7][C@@H:8]1[C:13](=[O:14])[O:15][C:10](=[O:12])[CH2:9]1)(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4]
Reactant: CC(=O)CC(=O)N[C@@H](CC(=O)O)C(=O)O
Agent: CS(=O)(=O)O
Solvent: CC(=O)O
Solvent: CC(=O)OC(C)=O
Solvent: CCOC(C)=O
Product: CC(=O)CC(=O)N[C@H]1CC(=O)OC1=O
Reaction time: 1.67 h

Procedure:
N-acetoacetyl-L-aspartic acid, 21.7 parts, was mixed with 20 parts by volume of glacial acetic acid and 12.3 parts of acetic anhydride. Methanesulfonic acid, 0.20 parts by volume, was added to the slurry and the mixture was stirred for 100 minutes. The mixture initially thinned and then became thicker. Dry ethyl acetate, 20 parts by volume, was added and the resulting slurry was stirred for an additional 20 minutes. A solid was collected on a filter under a nitrogen atmosphere, rinsed with dry ethyl acetate, and then dried in a vacuum dessicator at 0.1 mm to afford 16.3 parts of N-acetoacetyl-L-aspartic anhydride, identified by the NMR spectrum in dimethylsulfoxide-D6.
Reaction SMILES: [C:1](#[N:5])[CH2:2][C:3]#[N:4].[CH2:6]1[CH2:16]CN2C(=NCCC2)[CH2:8][CH2:7]1.BrCCCCBr>CN(C=O)C>[C:2]1([C:1]#[N:5])([C:3]#[N:4])[CH2:8][CH2:7][CH2:6][CH2:16]1
Reactant: C1CCC2=NCCCN2CC1
Reactant: N#CCC#N
Solvent: CN(C)C=O
Solvent: BrCCCCBr
Product: N#CC1(C#N)CCCC1
Temperature: 80 °C
Reaction time: 2 h

Procedure:
Malononitrile (15.0 g) was dissolved in dry DMF (200 mL) and cooled in an ice bath. Subsequently, DBU (75 mL, 2.2. equiv.) and 1,4-dibromobutane (29.6 mL, 1.1 equiv.) were added dropwise. The ice bath was removed, an extra 100 mL of dry DMF was added, and the mixture was stirred at 80° C. for 2 h. After cooling to ambient temperature, DCM was added and the mixture was washed 5 times with 5% aqueous NaHCO3. The organic phase was dried over Na2SO4 and evaporated under reduced pressure to give 40 g of a black oily substance. This was purified by flash chromatography eluting with PA:EA 9:1 (Rf=0.35, visualized with I2) to give 23.4 g of a colorless liquid. 1H NMR (400 MHz, CDCl3) δ 1.94-2.03 (m, 4H), 2.41 (t, J=7 Hz, 4H).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11]Br.[OH:13][C:14]1[CH:23]=[CH:22][C:17]([NH:18]C(=O)C)=[CH:16][CH:15]=1.[OH-:24].[Na+]>C(O)C>[NH2:18][C:17]1[CH:22]=[CH:23][C:14]([O:24][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][O:13][C:14]2[CH:15]=[CH:16][C:17]([NH2:18])=[CH:22][CH:23]=2)=[CH:15][CH:16]=1
Reactant: [OH-]
Reactant: BrCCCCCCCCCCBr
Reactant: CC(=O)Nc1ccc(O)cc1
Agent: [Na+]
Solvent: CCO
Product: Nc1ccc(OCCCCCCCCCCOc2ccc(N)cc2)cc1
Temperature: 0 °C

Procedure:
30 g (0.1 mole) of 1,10-dibromodecane and 38 g (0.25 mole) of p-hydroxyacetanilide were heated under reflux for 8 hours in the presence of 12 g of NaOH using ethanol. After the reaction, the resulting mixture was poured into ice water and the precipitate formed was collected, followed by washing with heated ethanol. The remaining brown crystal without purification was added in a mixed solvent of 100 ml of conc. HCl and 200 ml of ethanol and the system was heated under reflux for 2 hours. A solid remained after removing the solvent under reduced pressure which was dissolved in 2 l of ice water, and a 20% NaOH aqueous solution was added thereto to neutralize. The thus-precipitated solid was collected and recrystallized from ethanol to a pale brown grained crystal having a melting point of 70° to 71° C. at a yield of 18 g (51%). The crystal was identified as 1,10-bis(p-aminophenoxy)decane from its NMR spectrum and IR spectrum.
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][C@@:10]([CH2:21][CH:22]([CH3:24])[CH3:23])([CH2:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[C:9]1=[O:25])=O)(C)(C)C.C[O-].[Mg+2].C[O-].CO.O>C(O)(=O)C>[CH3:23][CH:22]([CH3:24])[CH2:21][C@@:10]1([CH2:13][C:14]([O:16][C:17]([CH3:18])([CH3:20])[CH3:19])=[O:15])[CH2:11][CH2:12][NH:8][C:9]1=[O:25]
Reactant: CC(C)C[C@@]1(CC(=O)OC(C)(C)C)CCN(C(=O)OC(C)(C)C)C1=O
Agent: C[O-]
Agent: [Mg+2]
Solvent: CO
Solvent: CC(=O)O
Solvent: O
Product: CC(C)C[C@@]1(CC(=O)OC(C)(C)C)CCNC1=O
Yield: 89.4 %

Procedure:
A solution of (S)-tert-butyl N-tert-butyloxycarbonyl-3-(2-methylpropyl)-2-oxo-3-pyrrolidineacetate (193 mg, 0.543 mmol), magnesium methoxide (3.0 mL, 6-10 wt. % in MeOH), and MeOH (2.7 mL) is stirred at room temperature for 16 hours. The solution is poured into water (15 mL) and the mixture acidified with acetic acid. The mixture is extracted several times with CH2Cl2, the combined filtrates dried (MgSO4), filtered, and concentrated to give 124 mg (89%) of the title compound as an oil.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[N:6]([CH2:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[CH:15][CH:14]=1)[CH2:5]2.[CH3:26][N:27]([CH3:31])[CH2:28][C:29]#[CH:30]>C(NC(C)C)(C)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[CH3:26][N:27]([CH3:31])[CH2:28][C:29]#[C:30][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[N:6]([CH2:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)=[CH:15][CH:14]=1)[CH2:5]2
Reactant: C#CCN(C)C
Reactant: O=C1c2ccc(Br)cc2CN1Cc1ccc(Oc2ccccc2)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CC(C)NC(C)C
Product: CN(C)CC#Cc1ccc2c(c1)CN(Cc1ccc(Oc3ccccc3)cc1)C2=O
Temperature: 100 °C
Reaction time: 2 h
Yield: 61.5 %

Procedure:
A mixture of 5-bromo-2-(4-phenoxy-benzyl)-2,3-dihydro-isoindol-1-one (0.100 g, 0.25 mmol), PdCl2(PPh3)2 (0.009 g, 0.013 mmol), and CuI (0.0025 g, 0.013 mmol) in diisopropylamine (4 mL) was treated with dimethyl-2-propynyl-amine (0.032 mL, 0.3 mmol). The reaction mixture was stirred at 100° C. for 2 h. After the complete consumption of bromo-isoindolone (monitored using GC-MS), the reaction mixture was cooled to ambient temperature and diluted with ethyl acetate (20 mL). The solids were removed by filtration and the filtrate was concentrated. Silica gel column chromatography of the resulting material using combinations of chloroform-methanol (typically 10:1 CHCl3-MeOH) afforded 5-(3-dimethylamino-prop-1-ynyl)-2-(4-phenoxy-benzyl)-2,3-dihydro-isoindol-1-one (0.061 g, 62%). 1H NMR (300 MHz, CDCl3): δ (ppm) 2.36 (s, 6H), 3.47 (s, 2H), 4.25 (s, 2H), 4.76 (s, 2H), 6.94-7.54 (m, 1H), 7.80 (d, 1H). GC-MS: 396 (M)+, 353 (M−43)+.